Neoehrlichiosis - a new tick-borne disease - is there a threat in Poland? - Epidemiological Review

PRZEGL EPIDEMIOL 2015; 69: 23 - 26 Problems of infections

© National Institute of Public Health – National Institute of Hygiene

Anna Moniuszko, Justyna Dunaj, Piotr Czupryna, Joanna Zajkowska, Sławomir Pancewicz

NEOEHRLICHIOSIS – A NEW TICK-BORNE DISEASE

– IS THERE A THREAT IN POLAND?

Department of Infectious Diseases and Neuroinfections, Medical University of Białystok, Poland

ABSTRACT

Recently in a few European countries a new pathogen transmitted by ticks Ixodes ricinus - Candidatus Neoeh-rlichia mikurensis was identified. It is a Gram negative intracellular bacterium belonging to the Anaplasmataceae family. Worldwide 23 cases were described, among which 16 in Europe. Infection with Candidatus Neoehrlichia mikurensis in humans runs mainly with fever, headache, nausea, arthralgia, thrombotic or haemorrhagic lesions, subcutaneous haemorrhages, haemorrhagic rash, general malaise, weight loss. The course of infection may be acute or chronic. The diagnosis is based on TaqMan real-time PCR, which allows for the detection of the gene coding for 16S rRNA and a blood smear. The drug of choice is doxycycline. Due to the fact that the Ixodes

ricinus ticks are common in Poland, there is a probability of infection with Candidatus Neoehrlichia mikurensis

among patients bitten by ticks. The possibility of non-symptomatic human infection Candidatus Neoehrlichia mikurensis in north-eastern Poland was shown, confirming the necessity to conduct research on a larger scale. Moreover, awareness of physicians about the possibility of infection in patients with non-specific symptoms after tick bite should be increased.

Key words: Candidatus Neoehrlichia mikurensis, Ixodes ricinus, Poland

INTRODUCTION

Common tick: Ixodes ricinus is the most important vector responsible for the spread of tick-borne diseases such as Lyme disease, tick-borne encephalitis (TBE), anaplasmosis and babesiosis in Europe, Asia and North America. Recently in several European countries, eg. in Sweden, Germany and Russia new pathogen transmit-ted by ticks Ixodes ricinus Candidatus Neoehrlichia mikurensis was identified (1,2,3). It is a Gram negative intracellular bacterium belonging to the family

Ana-plasmataceae.

Candidatus Neoehrlichia mikurensis species was

recently recognized in Europe as pathogenic for humans and seems to be second to Borrelia afzelii most com-monly transmitted by I. ricinus ticks pathogen in Central Europe. The presence of the bacteria was confirmed in various species of rodents in Europe and Asia (4,5).

I. ricinus ticks become infected by sucking the blood

of rodents, which developed symptomatic infection. The frequency of Candidatus Neoerlichia mikurensis detection in I. ricinus collected in Germany was 8.1%, the Czech Republic 10%, France 1.7%, Sweden 6.1%,

in Denmark 0.95%, in the Netherlands 7.9% and in Austria even 23.5% (1,6,7,8).

Infection of I. ricinus ticks, with this little-known pathogen was observed in Hungary (9) and Slovakia - 2.39% (10). In Poland, infection rate varies from 0.4% in the center of the country to 1.5% in the north-east (11).

Richter and Matuschka studied ticks removed from

the skin of people and found that 8.1% of I. ricinus ticks were infected with Candidatus Neoerlichia mikurensis, including 9.0% of nymphs and 4.5% of the adults. They also proved coinfection of Candidatus Neoerlichia mikurensis, Borrelia burgdorferi sensu stricto and B.

afzelii (6). Lommano et al. found that 3.3% of ticks

removed from birds were infected with Candidatus Neoerlichia mikurensis, which may suggest a role of birds in the spreading of the pathogen to new areas (12).

In 2008 Candidatus Neoehrlichia mikurensis was identified in raccoons (Procyon lotor) in Georgia and the USA (13) and in bank vole (14).

In Europe, the disease was described in 12 patients (2, 3, 15, 16). Less than half of the patients in Europe remembered tick bite. Most patients had splenectomy, hematological disorders or have been subjected to

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immunosuppressive therapy (15,16).Currently, it is suggested that in the case of symptomatic infection

Candidatus Neoehrlichia mikurensis use the name

“neoerhlichiosis” (15).

THE FIRST DESCRIBED CASE

The first described case of neoehrlichiosis was published in 2010 (16). A 77-year old male, has suf-fered from chronic lymphocytic leukaemia (B-cells) with autoimmune haemolytic anaemia treated with cor-ticosteroids since 2007. In the second half of 2008 due to the persistence of anaemia he was also treated with cyclophosphamide. In June 2009, after splenectomy, platelet count normalized. On the 3rd _{of July 2009, after} the kayak expedition, patient had diarrhoea, fever with chills, episode of loss of consciousness. He was admitted to hospital with a suspicion of sepsis (RR-85/60 mmHg, the temperature of 38.5 °C), accompanied by deep vein thrombosis of the lower limbs and the left pulmo-nary embolism. He was treated with ceftazidime and anti-thrombotic drugs. Etiologic agent of sepsis has not been established. In good general condition patient was discharged home. After a month the disease relapsed. The patient was hospitalized again. Developed a rash on the left leg, hypotension: RR-105/55 mmHg, fever up to 39.5 °C. Laboratory tests: HGB-8.5 g/dl, WBC-11 000/microlitr, CRP-54 mg/dL, Na+_{-134 mmol/dl.} He was treated with cloxacillin, meropenem. Multiple cultures (3 blood cultures, 2 urine cultures and 1 swab from the throat) were negative. On the August 21st _was discharged home with the recommendation of the use of loracarbef. On the 11th _{of September, despite antibiotic} therapy symptoms occurred again: fever with chills, infection of the upper respiratory tract, erysipelas of the right lower limb. In the treatment clindamycin was implemented. On the 22nd _{of September patient} symp-toms reappeared. Fever rose up to 39 °C. Laboratory tests revealed anaemia, leucocytosis, increased CRP concen-tration and procalcitonine, hyponatremia. Piperacykline, tazobactam and meropenem were included to the treat-ment, obtaining an improvement of general condition. The fever subsided, but muscle weakness of left upper limb remained. Head CT scan was normal/showed no abnormalities; blood cultures (aerobic and anaerobic) remained negative. Amplification of DNA from blood showed 100% concordance with Candidatus Neoeh-rlichia mikurensis by GenBank BLAST program. Tests performed on the samples from the preceding hospital-ization gave the same result. Treatment with doxycycline 2x100 mg was started. On the 5th _{of October the patient} was discharged home with normalization of laboratory parameters. Samples taken in November for check-up by PCR, showed no bacterial DNA in the blood (16).

SYMPTOMS

Infection with Candidatus Neoehrlichia mikurensis runs mainly with fever, headache, nausea, arthralgia, thrombotic or haemorrhagic complications, aneurysms, subcutaneous haemorrhages, haemorrhagic rash and weight loss. The infection may take an acute or chronic course. One fatal case was described. The longest de-scribed duration of symptoms was chronic relapsing fever manifested itself for 8 months in addition to the symptoms of thrombotic disease, inflammatory changes in the lungs, swelling of limbs and aching joints (2, 3, 15,16,17).

IMMUNODEFICIENCY

Most patients described in Europe suffered from autoimmune disorders (SLE, psoriasis, primary scle-rosing cholangitis, rheumatoid arthritis, chronic demy-elinating polyneuropathy) or haematological diseases, among which the most frequently observed are B-cell chronic lymphocytic leukaemia, chronic lymphocytic leukaemia, lymphoma, large B-cell disorders, post-transplant lymphoproliferative and proliferation of T-cell large granular lymphocyte. Almost all patients received corticoids, cyclophosphamide, rituximab, or tacrolimus treatment. Majority (8 out of 11) of these patients underwent splenectomy (3,18,19).

All of the 7 patients of 622 surveyed in China because of fever after a tick bite were immunocompetent in whom

Candidatus Neoehrlichia mikurensis was confirmed, no

patient was suffering from haematological disorders or autoimmune diseases. All patients were farmers, at the average age of 41 years. None of them have been vac-cinated against TBE, and the average time from the tick bite to the onset of symptoms was 8 days (2-35) (17). Similarly, described four cases of infection of healthy individuals concerned foresters without deviation in the immune system (20). The most common symptoms were nausea and vomiting (71% of patients), myalgia (57% of patients), arthralgia (28% of patients), stiff neck stiffness (57% of patients), cough (28% of patients), diarrhoea (14% of patients), erythema (14% of patients), confusion (14% of patients). In laboratory tests leukopenia (14% of patients), leucocytosis (14% of patients), thrombocytope-nia (28% of patients) were observed. Aminotransferases activity remained normal (17).

DIAGNOSTICS

Analysis of symptoms and laboratory tests may indicate a significant difference between infection in Europe and China.

Neoehrlichiosis – a new tick-borne disease ₂₅ No 1

Differences in laboratory between patients infected with Anaplasma phagocytophilum and Candidatus Neoehrlichia mikurensis are shown in Table I.

Table I. Differences between the results of laboratory tests

Anaplasma phagocytophilum infection and Candi-datus Neoehrlichia mikurensis

Anaplasma phagocytophilum Candidatus Neoehrlichia mikurensis Symptoms Similar WBC (10³/ mm3_{) Leucopenia Leucocytosis} PLT (10³/ /mm3_{) Severe}

trombocytopenia Mild trombocytopenia CRP (mg/dL) Increase 2-4 x Increase 10-15 x AspAT, AlAT (U/l) Increase Mild increase

IL-8 Normal Increase

The PCR, multiplex TaqMan real-time PCR for the detection of the gene coding for 16S rRNA and other such gro EL (heat shock operon) and a blood smear are used for diagnostics. There is neither possibility of the culture, nor appropriate serological methods due to cross-reactions. Often, based on laboratory tests

Candidatus Neoehrlichia mikurensis infection can

be assumed. Laboratory abnormalities suggestive of infection Candidatus Neoehrlichia mikurensis after tick bite shows leucocytosis, increased CRP, procalci-tonine, thrombocytopenia, anaemia, and hyponatremia (2,3,15 - 19).

TREATMENT

The drug of choice is doxycycline, also used in the infection with Borrelia burgdorferi and Anaplasma

phagocytophilum (3,15).

SUMMARY

Due to the fact that the Ixodes ricinus ticks are com-mon in Poland, there is a probability of infection with

Candidatus Neoehrlichia mikurensis among patients

bitten by ticks. Welc-Faleciak et al. showed the possibil-ity of human infection with Candidatus Neoehrlichia mikurensis in the north-eastern Poland (20), confirming the necessity of research on a larger scale. Moreover, awareness of physicians about the possibility of infec-tion in patients with non-specific symptoms after tick bite should be increased.

REFERENCES

1. Andersson M, Bartkova S, Lindestad O, et al. Co-infection with ‘Candidatus Neoehrlichia Mikurensis’

and Borrelia afzelii in Ixodes ricinus ticks in southern Sweden. Vector Borne Zoonotic Dis 2013; 13(7): 438-442.

2. Fertner ME, Mølbak L, Boye Pihl TP, et al. First detection of tick-borne “Candidatus Neoehrlichia mikurensis” in Denmark 2011. Euro Surveill 2012; 23:17(8).

3. von Loewenich FD, Geissdörfer W, Disqué C, et al. Detection of “Candidatus Neoehrlichia mikurensis” in two patients with severe febrile illnesses: evidence for a European sequence variant. J Clin Microbiol 2010; 48(7): 2630-2635.

4. Jahfari S, Fonville M, Hengeveld P, et al. Prevalence of Neoehrlichia mikurensis in ticks and rodents from North-west Europe. Parasit Vectors 2012; 19;5(1): 74. 5. Li H, Jiang J, Tang F, et al. Wide distribution and genetic

diversity of Candidatus Neoehrlichia mikurensis” in ro-dents from China. Appl Environ Microbiol 2013; 79(3): 1024-1027.

6. Richter D, Matuschka FR. Candidatus Neoehrlichia mikurensis, Anaplasma phagocytophilum, and Lyme Disease Spirochetes in Questing European Vector Ticks and in Feeding Ticks Removed from People. J Clin Mi-crobiol 2012; 50; 3: 943–947.

7. Michelet L, Delannoy S, Devillers E, et al. High-throughput screening of tick-borne pathogens in Europe. Frontiers in Cellular and Infection Microbiology 2014; 4: 1-13.

8. Derdáková M, Václav R, Pangrácova-Blaňárová L, et al. Candidatus Neoehrlichia mikurensis and its co-circulation with Anaplasma phagocytophilum in Ixodes ricinus ticks across ecologically different habitats of Central Europe. Parasit Vectors 2014; 7: 160.

9. Hornok S, Meli ML, Gönczi E, et al. First evidence of Candidatus Neoehrlichia mikurensis in Hungary. Parasit Vectors 2013: 17; 6(1): 267.

10. Pangrácová L, Derdáková M, Pekárik L, et al. Ixodes ricinus abundance and its infection with the tick-borne pathogens in urban and suburban areas of Eastern Slo-vakia. Parasit Vectors 2013; 16; 6(1): 238.

11. Welc-Falęciak R, Kowalec M, Karbowiak G, et al. Rickettsiaceae and Anaplasmataceae infections in Ixodes ricinus ticks from urban and natural forested areas of Poland. Parasit Vectors 2014 a; 24; 7: 121.

12. Lommano E, Dvořák C, Vallotton L, et al. Tick-borne pathogens in ticks collected from breeding and migratory birds in Switzerland. Ticks Tick Borne Dis 2014; 5(6): 871-82.

13. Yabsley MJ, Murphy SM, Luttrell MP, et al. Raccoons (Procyon lotor), but not rodents, are natural and experi-mental hosts for an ehrlichial organism related to “Can-didatus Neoehrlichia mikurensis”. Vet Microbiol 2008; 131(3-4): 301-308.

14. Vayssier-Taussat M, Le Rhun D, Buffet JP, et al. Can-didatus Neoehrlichia mikurensis in bank voles, France. Emerg Infect Dis 2012; 18(12): 2063-2065.

15. Maurer FP, Keller PM, Beuret C, et al. Close geographic association of human neoehrlichiosis and tick popula-tions carrying “Candidatus Neoehrlichia mikurensis” in eastern Switzerland. J Clin Microbiol 2013; 51(1): 169-176.

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16. Welinder-Olsson C, Kjellin E, Vaht K, et al. First case of human Candidatus Neoehrlichia mikurensis” infection in a febrile patient with chronic lymphocytic leukemia. J Clin Microbiol 2010; 48(5): 1956-1959.

17. Li H, Jiang JF, Liu W, et al. Human infection with Can-didatus Neoehrlichia mikurensis, China. Emerg Infect Dis 2012; 18(10): 1636-1639.

18. Grankvist A, Andersson PO, Mattsson M, et al. Infections with the tick-borne bacterium Candidatus Neoehrlichia mikurensis mimic noninfectious conditions in patients with B cell malignancies or autoimmune diseases. Clin Infect Dis 2014; 58(12): 1716-22.

19. Pekova S, Vydra J, Kabickova H, et al. Candida-tus Neoehrlichia mikurensis infection identified in 2 he-matooncologic patients: benefit of molecular techniques for rare pathogen detection. Diagn Microbiol Infect Dis 2011; 69(3): 266-70.

20. Welc-Faleciak R, Siński E, Kowalec M, et al. First cases of asymptomatic Candidatus Neoehrlichia mikurensis infection in immunocompetent humans Candidatus Neoehrlichia mikurensis. J Clin Microbiol 2014; 52(8): 3072-4.

Received: 3.12.2014

Accepted for publication: 30.12.2014

Address for correspondence:

Anna Moniuszko

Department of Infectious Diseases and Neuroinfections, Medical University of Białystok, Poland

Żurawia Street 14, 15-480 Bialystok Tel.: 00 48 85 7409514

fax: 00 48 85 7409515